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Cancer-associated fibroblasts endow stem-like qualities to liver cancer cells by modulating autophagy

Authors Zhao Z, Bai S, Wang R, Xiong S, Li Y, Wang X, Chen W, Cheng B

Received 12 December 2018

Accepted for publication 29 May 2019

Published 24 June 2019 Volume 2019:11 Pages 5737—5744

DOI https://doi.org/10.2147/CMAR.S197634

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Cristina Weinberg

Peer reviewer comments 2

Editor who approved publication: Dr Rituraj Purohit


Zhenxiong Zhao, Shuya Bai, Ronghua Wang, Si Xiong, Yawen Li, Xiju Wang, Wei Chen, Bin Cheng

Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People’s Republic of China

Purpose: Both cancer-associated fibroblasts (CAFs) and liver cancer stem cells (LCSCs) play an important part in the tumorigenesis, development and metastasis of hepatocellular carcinoma (HCC). Moreover, the stem-like properties in HCC cells could be promoted by CAFs. However, the mechanism remains largely unknown.
Patients and methods: We used conditioned medium (CM) of CAFs to culture Huh7 cells. Stemness of the cells was then examined mainly by sphere formation assay while stemness-associated genes including Nanog, Sox2 and Oct4 were measured by Western blotting. Immunofluorescence staining, Transmission Electron Microscope as well as Western blotting were performed to detect the level of autophagy in Huh7 cells.
Results: Increased level of stemness and autophagy was observed in HCC cells cultured in CAFs-CM compared to the control group. Activation of CAFs-induced autophagic flux could be inhibited by Chloroquine (CQ), which can accumulate LC3-II protein and increase punctate distribution of LC3 localization. Treatment of HCC cells with CQ effectively reversed the CAF-induced stemness, invasion, and metastasis ability in these cells. In vivo, Huh7 cells inoculated together with CAFs developed significantly larger tumors than Huh7 cells injected alone. Moreover, blockage of autophagy in Huh7 cells by CQ greatly reduced the growth of xenografted tumors of Huh7 cells combined with CAFs.
Conclusion: These results reveal that CAFs are capable of promoting stemness and metastasis of HCC cells and blocking autophagy could markedly attenuate the stemness enhanced by CAFs, suggesting that targeting autophagy in HCC could be an effective strategy in HCC treatment.

Keywords: cancer-associated fibroblasts, stemness, liver cancer, autophagy


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